The Role of Aryl Hydrocarbon Receptor (AHR) and AHR-Interacting Protein (AIP) in the Pathogenesis of Pituitary Adenomas

Pituitary adenomas (PA) are common endocrine neoplasia, generally presenting as sporadic diseases, with a multifactorial pathogenesis including somatic mutational events in cancer-related genes. However, genetic predisposition can currently be recognized in >5% of affected patients, mostly involving the Multiple Endocrine Neoplasia type 1 (MEN1) gene and the more recently identified Aryl hydrocarbon receptor Interacting Protein (AIP) gene, both being tumor-suppressor genes. Germline mutations in the AIP gene can be observed in a FIPA (Familial Isolated Pituitary Adenoma) context, but also in a minority of young patients with an apparently sporadic disease. Although the role of AIP in the pathogenesis of PA remains largely unknown, it is known to be mainly expressed by somatototrophs, with a loss-of-function and/or expression being documented in most AIP-mutated PA and in invasive somatotropinomas. The best characterized function of AIP is to stabilize the Aryl hydrocarbon Receptor, also known as the dioxin receptor, in the cytoplasm, but multiple interactions of AIP with other proteins involved in endocrine signalling and the regulation of cell cycle and apoptosis have been reported. In this chapter, current knowledge about the possible role of AhR and additional AIP-related proteins in pituitary tumorigenesis will be analysed.